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BLOCKADE OF CXCR2 AS A NOVEL APPROACH FOR CANCER CHEMOTHERAPY
by
Nidhi Sharda
A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(PHARMACEUTICAL SCIENCES)
May 2012
Copyright 2012 Nidhi Sharda

There is interplay between the malignant tumor cells and their non-malignant counterparts found in the microenvironment. This active bi-directional cross-talk between cancer cells and normal host cells has profound implications for tumor survival, proliferation and progression. Chemokines play a key role in cancer related inflammation and angiogenesis. Several evidences in chemokine system reveal that they affect multiple pathways of tumor progression including: leukocyte recruitment, neo-angiogenesis, tumor cell proliferation and survival, invasion and metastasis. Interleukin-8 or IL-8 is the prototype of the angiogenic chemokine family. IL-8 signaling plays a key role in development of tumor microenvironment and cancer progression. Angiogenesis, migration and chronic inflammation are key determinants of the process of tumorigenesis and tumor proliferation. We have used SCH-527123, an anti-inflammatory agent used for the treatment of asthma, as a prototype compound to determine whether this is a good target for anticancer drug development. We assessed growth inhibition and migration by MTT and colony formation assay and wound healing scratch assay in breast cancer cellular model. We studied effect on angiogenesis by tube formation assay on HMEC endothelial cells. We have confirmed anti-angiogenic and anti-migration activity as a consequence of CXCR1/2 receptor blockade, as seen from gene expression data. ❧ In conclusion, our data in the breast cancer model showed that SCH-527123 has potential anti-cancer properties. The cytotoxic activity may be not being linked to its anti-activity since higher concentrations are necessary to achieve IC50. These findings need to be verified in xenograft tumor bearing models.. Future studies in co-culture experiments with neutrophils, condition media, which simulate tumor microenvironment may provide information as to the role of tumor microenvironment in cancer proliferation.

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BLOCKADE OF CXCR2 AS A NOVEL APPROACH FOR CANCER CHEMOTHERAPY
by
Nidhi Sharda
A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(PHARMACEUTICAL SCIENCES)
May 2012
Copyright 2012 Nidhi Sharda